The central role of Src in the development of several malignancies including breast cancer and the accumulating evidence of its interaction with receptor tyrosine kinases (RTK), integrins and steroid receptors have identified it as an attractive therapeutic target. In the current study we have evaluated the effect of a Src/Abl kinase inhibitor SKI-606, on breast cancer growth, migration, invasion and metastasis. Treatment of human breast cancer cells MDA-MB-231 with SKI-606 caused a marked inhibition of cell proliferation, invasion and migration by inhibiting MAPK and Akt phosphorylation. For in vivo studies MDA-MB-231 cells transfected with the plasmid encoding green fluorescent protein (GFP) [MDA-MB-231-GFP] were inoculated into mammary fat pad of female BALB/c nu/nu mice. Once tumor volume reached 30-50 mm3, animals were randomized and treated with vehicle alone or 150 mg/kg of SKI-606 by daily oral gavage. Experimental animals receiving SKI-606 developed tumors of significantly smaller volume (45-54%) as compared to control animals receiving vehicle alone. Analysis of lungs, liver and spleen of these animals showed a significant decrease in GFP positive tumor metastasis in animals receiving SKI-606 at a dose that was well tolerated. Western blot analysis and immunohistochemical analysis of primary tumors showed that these effects were due to the ability of SKI-606 to block tumor cell proliferation, angiogenesis, growth factors expression and inhibition of Src mediated signalling pathways in vivo. Together the results from these studies provide compelling evidence for the use of Src inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.112641 |
| Date | January 2007 |
| Creators | Jallal, Houda. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002699465, proquestno: AAIMR51287, Theses scanned by UMI/ProQuest. |
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